Authors:
H Xu, M Di Antonio, S McKinney, V Mathew, B Ho, NJ O'Neil, ND Santos, J Silvester, V Wei, J Garcia, F Kabeer, D Lai, P Soriano, J Banáth, DS Chiu, D Yap, DD Le, FB Ye, A Zhang, K Thu, J Soong, S-C Lin, AHC Tsai, T Osako, T Algara, DN Saunders, J Wong, J Xian, MB Bally, JD Brenton, GW Brown, SP Shah, D Cescon, TW Mak, C Caldas, PC Stirling, P Hieter, S Balasubramanian, S Aparicio
Journal name: 
Nat Commun
Citation info: 
8:14432
Abstract: 
G-quadruplex DNAs form four-stranded helical structures and are proposed to play key roles in different cellular processes. Targeting G-quadruplex DNAs for cancer treatment is a very promising prospect. Here, we show that CX-5461 is a G-quadruplex stabilizer, with specific toxicity against BRCA deficiencies in cancer cells and polyclonal patient-derived xenograft models, including tumours resistant to PARP inhibition. Exposure to CX-5461, and its related drug CX-3543, blocks replication forks and induces ssDNA gaps or breaks. The BRCA and NHEJ pathways are required for the repair of CX-5461 and CX-3543-induced DNA damage and failure to do so leads to lethality. These data strengthen the concept of G4 targeting as a therapeutic approach, specifically for targeting HR and NHEJ deficient cancers and other tumours deficient for DNA damage repair. CX-5461 is now in advanced phase I clinical trial for patients with BRCA1/2 deficient tumours (Canadian trial, NCT02719977, opened May 2016).
DOI: 
http://doi.org/10.1038/ncomms14432
Research group: 
Caldas Group, Brenton Group, Balasubramanian Group
E-pub date: 
17 Feb 2017